In chronic lymphocytic leukemia (CLL), scientists investigated why some patients eventually stop responding to BTK degraders, a newer class of drugs designed to destroy the BTK protein rather than merely block its activity. BTK is part of a signaling pathway that helps malignant B cells survive and multiply. Early trials of degraders such as zelebrudomide and bexobrutideg produced response rates above 80% among patients whose disease had already resisted other therapies, but resistance still emerged in some cases.

By analyzing tumor samples from treated patients, an MSK-led team identified a mutation known as BTK A428D in several tumors that became resistant. The mutation was not necessarily created by treatment; in some patients, small populations of A428D cells were already present before therapy began. As the degrader eliminated drug-sensitive leukemia cells, those resistant cells gained a competitive advantage and expanded. The researchers found that venetoclax, an established leukemia drug, could be combined with BTK degraders to target both mutant and nonmutant cancer cells in laboratory experiments, raising the possibility of a future clinical trial.

Another MSK study examined why bone is such a challenging destination for metastatic cancer. The researchers found that the physical hardness of bone may act as an immune warning signal. When cancer cells encounter a rigid environment, they become mechanically stiffer. That change can make them more vulnerable to natural killer cells and cytotoxic T cells, immune cells that destroy abnormal targets by releasing toxic molecules and triggering cell death. In mouse models, animals lacking effective immune defenses developed extensive bone metastases, while animals with intact natural killer and T-cell responses largely resisted colonization.

The investigators also identified osteopontin, or SPP1, as a critical molecule in the process. Cancer cells producing high levels of osteopontin were better able to adapt to bone-forming environments and establish metastatic sites. Human melanoma data added a surprising layer: tumors with high osteopontin activity and mechanically stiff cancer cells often contained fewer immune cells. The researchers interpret this pattern as evidence of “mechanosurveillance,” in which immune cells respond not only to chemical signals but also to the physical properties of cancer cells. In tumors with strong immunity, stiff cells may be eliminated; where immune defenses are weak, they can survive and accumulate.

Smoking cessation was the focus of a randomized trial involving 306 people diagnosed with cancer within the previous four months. Conducted through ECOG-ACRIN and co-led by MSK and Mass General Brigham investigators, the trial compared usual care with a sustained telehealth intervention. Patients in the intervention group received as many as 11 video counseling sessions addressing motivation, cravings, stress management, and relapse prevention, along with free nicotine patches and lozenges for up to 12 weeks. After six months, 28% had stopped using tobacco, compared with 15% who received only information about quitline and cessation resources. The program also helped many participants who did not quit completely reduce their daily tobacco use, demonstrating that virtual support can reach patients treated in community hospitals far from major cancer centers.

At the molecular level, MSK structural biologists produced the first detailed three-dimensional images of SLC34A2, a transporter that controls phosphate movement across cell membranes. Phosphate is essential for energy metabolism, bone formation, and cellular signaling, but excessive blood phosphate can contribute to kidney failure, cardiovascular damage, and abnormal calcium deposits. Using cryo-electron microscopy, the researchers captured the transporter in several functional states and discovered that it operates differently from the classic “alternating access” mechanism used by many membrane transporters.

Rather than moving its phosphate-binding region back and forth across the membrane, SLC34A2 appears to keep that region relatively stable while a surrounding gate opens and closes. This structural information shows how an existing inhibitor binds to the transporter and could help researchers design more precise drugs. SLC34A2 is overproduced in an estimated 80% to 90% of ovarian tumors and is being investigated as a therapeutic target. The protein is also relevant to chronic kidney disease, which affects more than 800 million people worldwide and is often associated with disrupted phosphate regulation.

A separate analysis of more than 35,000 cancer patients examined whether Medicare Advantage insurance affects the quality, speed, or cost of cancer care. The investigators compared patients enrolled in Medicare Advantage with those receiving traditional Medicare across 13 treatment scenarios, including metastatic colon cancer, multiple myeloma, and advanced prostate cancer. They evaluated actual treatments against National Comprehensive Cancer Network guidelines and linked those treatments to Medicare reimbursement data. Medicare Advantage patients were just as likely to receive guideline-concordant care, and treatment began after a median of 36 days, compared with 35 days for traditional Medicare. At the same time, estimated treatment costs were about 6% lower, or approximately $931 per patient, suggesting that savings may come from selecting less expensive options that remain clinically appropriate rather than from reducing treatment quality.

MSK neurosurgeons also investigated how much brain tissue should be removed when tumors cause temporal-lobe epilepsy. These tumors can trigger recurrent seizures, but aggressive surgery may damage regions involved in language and memory. Reviewing seven studies involving 277 patients, the researchers found that complete removal of the tumor itself was the strongest predictor of seizure control. Patients with only partial tumor removal were more likely to experience continuing seizures and tumor regrowth. Removing additional healthy brain tissue beyond the lesion, however, did not consistently improve seizure outcomes. Cognitive effects varied, although removal of the entire hippocampus, tumors on the left side of the brain, and deeply located temporal tumors were associated with greater risks to verbal memory.

Together, the findings illustrate how modern cancer research is expanding beyond the search for new drugs. Resistance can arise from rare mutant cells already hidden within a tumor; metastatic disease can be shaped by the mechanical stiffness of tissue; and immune cells may read physical signals as readily as molecular ones. At the same time, behavioral programs delivered through video technology, structural images of membrane proteins, carefully measured insurance outcomes, and more conservative surgical strategies are opening additional paths toward more effective and safer care.

Subject of Research: Cancer biology, leukemia drug resistance, bone metastasis, tobacco cessation, phosphate transport, cancer care costs, and epilepsy surgery.

Article Title: Memorial Sloan Kettering Research Reveals New Insights Into Drug-Resistant Leukemia, Bone Metastasis, Smoking Cessation, Phosphate Transport, Cancer Care, and Tumor-Related Epilepsy

Web References: https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-26-0251/786984/Molecular-and-Structural-Basis-of-Pan-Resistance; https://www.cell.com/immunity/fulltext/S1074-7613(26)00276-1; https://ascopubs.org/doi/abs/10.1200/JCO-25-02267; https://www.pnas.org/doi/abs/10.1073/pnas.2602077123; https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2851378; https://www.sciencedirect.com/science/article/pii/S1525505026002891

References: Cancer Discovery; Immunity; Journal of Clinical Oncology; Proceedings of the National Academy of Sciences; JAMA Internal Medicine; Epilepsy & Behavior.

Image Credits: Memorial Sloan Kettering Cancer Center

Keywords: Cancer research, chronic lymphocytic leukemia, BTK degraders, BTK A428D, venetoclax, bone metastasis, osteopontin, mechanosurveillance, immunology, smoking cessation, telehealth, SLC34A2, phosphate transporter, ovarian cancer, kidney disease, Medicare Advantage, epilepsy surgery, brain tumors

The study reveals that the ubiquitous oncogene MYC, well-known for its role in driving various cancers, induces the expression of USP10, an enzyme responsible for removing ubiquitin tags from specific proteins, thereby stabilizing them. Ubiquitination is a critical cellular process that typically marks proteins for degradation; thus, USP10’s action prolongs the lifespan and functional activity of its target proteins. Critically, the researchers have identified SOX4, a transcription factor implicated in cell fate decisions and developmental processes, as a primary target of USP10 in thymocytes.

Thymocytes, the precursor cells in the thymus responsible for generating functional T cells, undergo tightly regulated proliferation and differentiation. Disruption in these processes often leads to malignant transformations and the development of leukemia. The Zhang and colleagues’ research shows how MYC-driven upregulation of USP10 leads to enhanced stabilization of SOX4 protein, which in turn promotes excessive thymocyte proliferation—a hallmark of leukemic transformation in the murine model.

One of the seminal findings of this study is the demonstration of the mechanistic pathway through which MYC exerts oncogenic influence beyond direct gene activation. Rather than simply upregulating SOX4 transcription, MYC manipulates the protein homeostasis machinery by elevating USP10 levels, which acts post-translationally to preserve SOX4 from proteasomal degradation. This finding underscores the complexity of MYC’s oncogenic network and its capacity to employ diverse strategies to sustain malignant cell survival and proliferation.

Using advanced mouse models that recapitulate human leukemia phenotypes, the authors employed precise genetic and biochemical approaches to delineate the MYC-USP10-SOX4 axis. Through a series of elegant experiments combining chromatin immunoprecipitation (ChIP), RNA sequencing, and protein stability assays, they convincingly demonstrated the direct regulation of USP10 by MYC. Moreover, they revealed how USP10’s enzymatic activity specifically targets ubiquitin conjugates on SOX4, stabilizing its presence within the thymocyte nucleus.

Importantly, the stabilization of SOX4 was shown to reinforce transcriptional programs that favor thymocyte proliferation and impede normal differentiation cues. SOX4’s downstream targets include critical regulators of the cell cycle and apoptosis, thus its deregulated expression results in unchecked cell division and survival—hallmarks of leukemogenesis. The findings provide a conceptual framework explaining how an oncogenic transcription factor can exploit protein modification pathways to reprogram hematopoietic progenitors.

Beyond these mechanistic discoveries, clinical implications of this research are profound. Leukemia remains a formidable challenge in oncology, with many subtypes associated with poor prognosis and treatment resistance. The identification of USP10 as a crucial mediator in this pathway offers a novel molecular target. Pharmacological inhibitors of deubiquitinases, including USP10, are currently under development, and this study highlights their potential utility in inhibiting SOX4 stabilization and curtailing leukemia progression.

The research team also conducted in vivo therapeutic experiments employing USP10 inhibitors in leukemic mice, demonstrating significant reduction in thymocyte proliferation and delayed leukemia onset. These preclinical results emphasize the translational potential of targeting the USP10-SOX4 interaction, suggesting that disrupting this axis could complement existing chemotherapy and targeted treatments for T-cell leukemias.

Furthermore, this work builds on the expanding understanding of deubiquitination pathways as critical regulators of protein function in cancer. Unlike the extensively studied ubiquitin ligases, whose role is to tag proteins for degradation, deubiquitinases like USP10 remove these tags, thereby fine-tuning protein stability and activity. This dual regulatory system is increasingly recognized as essential for cellular homeostasis, and its dysregulation is a frequent driver of oncogenic processes.

The focus on the thymic environment and T-cell development in this study is particularly noteworthy, as leukemia originating from T-cell precursors is notably aggressive and difficult to treat. By elucidating the molecular triggers within thymocytes themselves, the researchers address a critical gap in leukemia biology. Their work provides an unprecedented insight into how early progenitor cells become hijacked by oncogenic signals at the protein regulatory level.

From a technological perspective, the study leveraged state-of-the-art proteomic analyses to quantify ubiquitination changes and employed CRISPR-based genetic tools to selectively manipulate MYC, USP10, and SOX4 expression in thymocytes. These methodologies allowed for precise dissection of the signaling cascade, validating the causal relationships and excluding confounding variables—a rigorous approach that enhances the credibility of the findings.

Moreover, this investigation highlights the importance of systems biology approaches in understanding cancer. The interplay between transcriptional regulation, post-translational modification, and protein stability comprises a complex network that dictates cell fate decisions. By piecing together the MYC-USP10-SOX4 pathway, the authors contribute a vital puzzle piece to the broader landscape of oncogenic regulatory circuits.

Future research directions inspired by this study may include exploration of how this pathway interacts with other known leukemia-associated mutations, identification of biomarkers predictive of USP10 activity, and assessment of combination therapies that concurrently target multiple nodes in the pathway. In-depth analysis of human leukemia samples for expression patterns of MYC, USP10, and SOX4 will also be crucial to validate the clinical relevance of these findings in human patients.

Collectively, this transformative research elucidates an unrecognized axis in leukemia biology, elucidating how MYC orchestrates a post-translational stabilization mechanism via USP10 to maintain SOX4 levels, fueling malignant thymocyte expansion. The integration of molecular biology, genetics, and preclinical therapeutics in this study sets a new benchmark for research aimed at uncovering cancer vulnerabilities.

In conclusion, the discovery that MYC-induced USP10 activity stabilizes SOX4 to promote thymocyte proliferation and leukemia onset marks a significant advance in our understanding of cancer pathogenesis. By bridging oncogenic transcription programs with protein modification pathways, this work not only deciphers complex cell regulatory mechanisms but also points the way to innovative treatment strategies that may improve outcomes for leukemia patients worldwide.

Subject of Research: Mechanistic role of MYC-induced USP10 in stabilizing SOX4 to promote thymocyte proliferation and leukemia onset in mice.

Article Title: MYC-induced USP10 stabilizes SOX4 to promote thymocyte proliferation and leukemia onset in mice.

Article References:

Zhang, M., Wu, H., Lin, X. et al. MYC-induced USP10 stabilizes SOX4 to promote thymocyte proliferation and leukemia onset in mice.
Nat Commun (2026). https://doi.org/10.1038/s41467-026-71084-w

Image Credits: AI Generated

Asparaginase has played a pivotal role in the treatment of acute lymphoblastic leukemia since its FDA approval in the 1970s. Despite its significance in cancer therapy, the existing formulations of asparaginase are notorious for their adverse side effects, including severe blood clots and liver damage. These complications have restricted the drug’s use to a limited subset of patients, often forcing oncologists to make difficult decisions regarding treatment plans. The research team is acutely aware of these challenges and has set themselves on a course to address them head-on, thereby advancing the therapeutic potential of asparaginase for a broader patient population.

The novel enzyme developed by the UIC team seeks to augment the efficacy of asparaginase while significantly reducing the associated risks. By leveraging advanced protein engineering techniques, they have created a biologic compound that preserves the enzyme’s anticancer properties while minimizing the toxic effects that have plagued traditional formulations. This optimization process not only enhances the drug’s therapeutic index but also raises the prospect of utilizing it in the treatment of other malignancies, such as melanoma and liver cancer. As such, the research represents a promising leap towards developing more versatile cancer therapies.

In a recent publication in the journal Cancer Letters, Lavie and his collaborators reported compelling findings from preclinical studies conducted on animal models. Their innovative enzyme demonstrated impressive efficacy, successfully obliterating leukemia cells in mice while sparing them from the debilitating side